Our research is focused on revealing the molecular mechanisms that underlie the perception of pain. Sensation of painful stimuli is critical for the survival of the organism. However, acute and chronic pain affects hundreds of millions of people as a result of injury, and is a major symptom in many illnesses. Unfortunately, currently available drug based therapies have numerous deleterious side effects and/or potential for abuse and addiction, while also not being effective in the treatment of persistent pain. Despite great advances, much remains to be understood about how painful or noxious stimuli are perceived and coded by the nervous system. Here we propose to use the zebrafish system to conduct a forward genetic screen to elucidate the fundamental properties of the neural circuits required for the sensation of pain. We have developed specific transgenic tools to examine the development and function of specific neuronal populations that detect modality specific nociceptive stimuli. We propose to use these tools to characterize genetic mutations that alter the behavioral response to heat, cold, mechanical or chemical irritants. Our preliminary data demonstrate that we can identify mutations affecting distinct pain modalities. We expect that this genetic screen will provide a resource for the community interested in the development of neural circuits and the perception of pain, and may provide targets for potential therapies for debilitating painful conditions.